The challenges and goals for the next phase of genetic research on alcohol dependence (AD) will be to i) confirm candidate genes, ii) to understand the mechanism(s) of action for individual genes in AD and iii) to use the molecular and genetic information to identify potential targets for novel interventions in AD. As a strategy to approach these complex goals, we have formulated three major organizing hypotheses that integrate and direct the individual components of this Developmental (P20) application. These include: 1. A focus on gene networks rather than individual genes which will provide mechanistic information, target identification and cross-species validation of molecular events affecting alcohol-related behaviors and risk for AD. 2. A bi-directional cross-species gene discovery and validation scheme that can provide both powerful confirmation of candidate genes and mechanistic information. Our planned studies in mice (Project 1), humans (Project 2, Pilot 2), C. elegans (Project 3), and D. melanogaster (Pilot 1) will be mutually reinforcing. 3. Initial sensitivity and acute tolerance to ethanol are phenotypes with broad cross-species experimental applicability and validated relevance to AD. For this project, for which we request four years of support, we outline a series of three developmental and two pilot projects which form a highly integrated and novel approach that implement the hypotheses outlined above. An Administrative Core and Bioinformatics Core will provide needed support across projects. The Specific Aims of individual projects will include developmental aspects that seek to broaden our scientific base, increase integration between Center components and extend our experimental models to eventually include additional behavioral phenotypes such as acute and chronic tolerance and dependence. We expect novel contributions to the field of alcohol research from our cross-species analysis of acute ethanol effects.